Coumarin and its derivatives are principal oral anticoagulants. Coumarin is
water insoluble, however 4-hydroxy substitution confers weakly acidic properties
to the molecule that makes it water soluble under slightly alkaline conditions
(Equation below).

The structures of coumarin and its derivatives are as shown below. Warfarin is
marketed as the sodium salt. It has one chiral center. The S(-) isomer is about
5 - 8 times more potent than the R(+) isomer, however, commercial warfarin is a
racemic mixture. Click on the appropriate hyperlinks to visualize the
three-dimensional structures of individual coumarins.

Coumarin and 4-hydroxycoumarin do not possess anticoagulant activity. Link, who
pioneered the isolation and characterization of bihydroxycoumarin (dicoumarol)
from sweet clover, concluded that the minimal requirements for anticoagulant
activity are 4-hydroxy group, a 3-substituent, and a bis molecule (see below).

Coumarins exert their effect in vivo only after a latent period of 12 to 4 hours
and their effect lasts for 1.5 to 5 days. The observed slow onset may be due to
the time required to decrease predrug prothrombin blood levels, whereas the long
duration of action observed with warfarin may be due to the lag time required
for the liver to resynthesize prothrombin to predrug blood levels.

Coumarins and 1,3-indandiones (later section) interact with certain drugs. For
example, the action of oral anticoagulants can be enhanced by drugs such as
phyenylbutazone and salicylates while antagonized by barbiturates and vitamin K.

Coumarins are competitive inhibitors of vitamin K in the biosynthesis of
prothrombin.

The
coagulation cascade relies on the conversion of prothrombin
to thrombin in a very important step. However, this conversion depends on the
presence of 10 g-carboxyglutamic
acid (GLA) residues in the N-terminus of prothrombin. The multiple Gla residues
form a binding site for Ca+2. Under normal circumstances 10 glutamic
acid (Glu) residues of prothrombin are converted to Gla residues in a
post-translational modification.

This post-translation modification is catalyzed by an enzymes vitamin K
reductase and vitamin K epoxide reductase. Vitamin K is a co-factor in this
conversion reaction. Thus it cycles between a reduced form and an epoxide form.
Because of their structural similarity with vitamin K coumarins are thought to
bind the enzymes, vitamin K reductase and vitamin K epoxide reductase, without
facilitating the conversion of Glu residues of prothrombin to Gla. Thus
prothrombin cannot be acted upon by factor Xa.